Certain 7-(beta-oxy-gamma-(n**4-benzyl-piperazino)-propyl-theophyllines

ABSTRACT

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF:   1,3-DI(CH3-),2,6-DI(O=),7-((4-R-PIPERAZINO)-CH2-CH(-O-R&#39;&#39;)-   CH2-)-1,2,3,6-TETRAHYDROPURINE   THE ACID-ADDITION SALTS AND QUATERNARY AMMONIUM SALTS THEREOF, WHEREIN R IS SELECTED FROM THE GROUP CONSISTING OF BENZYL, METHYLBENZYL, ISOPROPYLBENZYL, CHLOROBENZYL AND PHENYLETHYL, AND R&#39;&#39; IS SELECTRED FROM THE GROUP CONSISTING OF HYDROGEN, ACETYL AND BENZYL.

United States Patent This application is a continuation of applicationSer. No. 510,099, Nov. 26, 1965.

The present invention relates to theophylline derivatives represented bythe following general formula:

(III) wherein Y represents a lower alkylene chain having two or morecarbon atoms, but in case of a lower alkylene chain of more than threecarbon atoms, it may contain hydroxyl group or an acyloxy group at theposition of the carbon atom which does not directly combine withnitrogen atom, and

R represents hydrogen, a lower alkyl, a lower hydroxylalkyl, a loweraralkyl, a lower aralkyl containing a member selected from the groupconsisting of halogen lower alkyl and lower alkoxy as a substituent inthe aromatic nucleus, a lower alkenyl, a lower naphthyl alkyl, :1 lowerZ-pyridyl alkyl, a group COX or a group SOQZ, wherein X represents amember selected from the group consisting of hydrogen, lower alkyl,lower alkoxy, ary] and aralkoxy and Z represents a member selected fromthe group consisting of a lower alkyl, aryl and lower aralkyl,

and also to their salts.

The present invention relates also to a process for preparing theaforementioned theophylline derivatives and their salts.

An object of the present invention is to provide excellent medicineshaving coronary dilating effect. For hitherto known theophyllinederivative having the same eflect, it may be mentioned7-(fl-benzoyloxy-'y-diisobutylaminop ro pyl theo phyl line.

The compounds of the present invention have a satisfactory coronarydilating efiect equal to or more than the aforesaid known theophyllinederivative. In particular,

"ice

acylated compounds of the present invention have more increasedpharmaceutical activity, a compound in which R is aralkyl group and Y isacyloxy group, for example, shows 2-5 times activity comparing withaforesaid known theophylline derivative.

Another object of the present invention is to provide processes forproducing advantageously the theophylline derivatives of the presentinvention and their salts.

According to the present invention, aforesaid medicines may be preparedby the following procedures.

(A) In general, reaction between the compound (I) of the formula:

0 t N ILC-N N N/ and the compound (II) of the formula:

B-H-R wherein one of A and B represents hydrogen and another representsthe group which react with said hydrogen to form alkylene group (Y), forexample, haloalkyl (may have hydroxyl group or acyloxy group) orepoxyalkyl group, R and Y are as defined above.

(B) A part of the present compounds may be obtained by the followingprocedures.

(a) A compound (III) of abovementioned general formula in which R is H,that is, a compound of the formula:

0 r-Em wherein Y is as defined above and R, represents a group -COX or agroup SO Z (wherein X and Z are as defined above).

(b) A compound (III) :of abovementioned general formula in which R is alower alkyl, a lower hydroxyalkyl, a lower aralkyl, a lower aralkylcontaining a member selected from the group consisting of halogen, loweralkyl and lower alkoxy as a substituent in the aromatic nucleus, a loweralkenyl, a lower naphthylalkyl or 2- pyridyl alkyl, that is, a compoundof the formula:

compound in which R is H, that is, a compound of the formula:

wherein Y is as defined above, and a compound (IV) which react with saidcompound to form R that is to say, a halide, epoxy compound or vinylcompound having R, as fundamental skeleton.

(C) A compound (III) in which Y has acyloxy group may be also producedby usual acylation of a compound in which Y has hydroxyl group.

(D) Salts of the compound (III) may be produced by any conventionalmethod.

The above mentioned processes will be explained more in detail asfollows.

The condensation reaction between the compounds (I) and (II) in theprocess (A) is occasionally carried out in the absence of solvent.However, it is preferable to carry out the reaction under heating in thepresence of solvent, for example, such as methanol, ethanol, isopropylalcohol, benzene, toluene, xylene, dioxane, chloroform, carbontetrachloride ethylene dichloride. The compounds (I) and (II) may beadvantageously used in equal mol but in case A where the compound (I) isa haloalkyl group the yield would be improved by use of two times theequivalent of compound (II). In the case where either A or B is ahaloalkyl group it is advisable to use as an dehydrohalogenating agentan inorganic alkali such as sodium hydroxide, potassium hydroxide, or aninorganic alkali metal salt such as anhydrous sodium carbonate or anorganic tertiary amine, such as triethylamine. In particular sincetriethylamine acts also as a solvent it may be advantageously used. Incase B, if compound (II) is a haloalkyl group A, compound (I) may be ofan alkali metal atom.

For carrying out the method (B-a) the following three (1, 2, 3)procedures may be adopted. (1) Hydrolysis by means of mineral acids suchas hydrochloric acid, sulfuric acid or inorganic alkalis such as causticsoda, caustic 4 p I potassium or inorganic alkali metal salts such ananhydrous sodium carbonate, (2) elimination of R at room temperature orunder heating in hydrogen bromide-acetic acid, (3) catalytic reductionby means of catalyst such as palladium urea, Raney nickel.

In carrying out the method (B-b), as the compound (IV), for example,ethyl chloride, ethylene oxide, 2vinyl pyridine, isopropylbenzylchloride, butyl bromide, allylbromide, p-methoxybenzyl chloride,p-chlorobenzyl chloride and the like may be used to give respectivelycorresponding compounds. Although the reaction proceeds in the absenceof solvent, the reaction is preferably carried out in the presence of asolvent. For the solvent, it may be mentioned, for example, methanol,ethanol, isopropyl alcohol, benzene, toluene, dioxane, chloroform,carbon tetrachloride and the like. The reaction is advantageouslycarried out under heating. In general, the compound where R is H andcompound (IV) may be used in eqizalinol amounts. In the case wherecompound (IV) is a halide, an inorganic alkali metal salts such asanhydrous sodium carbonate or tertiary amines such as triethylamine maybe advantageously used as dehydrohalogenating agent. Particularly sincetriethylamine also acts as a solvent, it may be advantageously employed.Where compound (IV) is a vinyl compound, higher yield may be expected ifglacial acetic acid is used as a solvent.

For an acylating agent in the method"(C) it may be mentioned aliphaticcarboxylic halides, for example, such as acetyl chloride,propionyl-chloride, phenylacetic chloride, aliphatic carboxylic acidanhydride, for erample, such as acetic anhydride, aromatic carboxylicchloride, for example, such as benzoyl chloride or organic carboxylicacid anhydride, for example, such as benzoic anhydride. The reaction ispreferably carried out in the presence of a solvent which does not takepart in the reaction, for example, benzene, ether, pyridine, toluene,xylene, ligroine, petroleum benzine, petroleum ether, chloroform, carbontetrachloride, ethylene dichloride and the like. If a liquid acidanhydride is used as acylating agent, a solvent is not required.Although the reaction may be carried out at either room temperature orunder heating, it is advisable to carry out the reaction under heatingbecause it proceeds in a shorter time. In order to facilitate thereaction and to make the yield higher, zinc chloride, anhydrous sodiumacetate, sulfuric acid, and the like, may be used as a catalyst.

The salts in the method (D) may be produced by my conventional methods.These salts are mineral acidsalt's, for example, such as hydrochloride,hydrobromide, phosphate, nitrate and organic acid salts, for example,such as maleate, fumarate, citrate, tartrate succinate,methanesulfonate, ethanedisulfonate, p-toluenesulfonate, and the like.Further, quaternary ammonium salt may be produced by reactive withmethyl iodide.

The processes for producing the compounds of this invention areexplained by the following examples:

EXAMPLE 1 To a mixture of 8.6 g. of 7-(fl-bromoethyD-theophylline and9.0 g. of butylpiperazine were added ml. of ethanol. The mixture wassubjected to reflux for 6 hours under heating and stirring. Aftercompletion of the reaction ethanol was distilled oil and the residue wasdissolved in chloroform, washed with water and dried. After removal ofchloroform by distillation 10.5 g. of 7-[B-(N-butylpirazino)-ethyl]-theophylline were obtained. Recrystallize fromligroine yielded a pure product. MP. 77 79 C.

Elemental analysis-Calculated as C H N O (percent): C, 58.60; H, 8.10;N, 24.12. Found (percent): C, 58.79; H, 7.89; N, 24.34. I

EXAMPLES 2-5 The following products were obtained by the same manner asin Example 1.

TABLE 1 Reaetants Example H16 N R (g.) Number Product Th.'-A (g.)

2 7-lfl-(N -allyLpiperazino)-ethyl]-theo- A: R:

phylllne.

-CHr-CH:BI.' OHGH=CH;

3 7-[B-[N*-(r-hydroxy-propyl)-plperaz1no- A: R:

ethyll-theophylllne.

-CHz-CH:B1 CH2CHr-CH:OH

4 7-lB-(N -chlorobenzyl)-piperazlno- A: R:

ethyll-t eophylline.

C II OH -Br -C1l 01 6 7-[1-lN US-h dmXyeth l)-plperazino A: R:

propyH-thoophylline.

-CHz-CH3CH2B1' CH2CH2-0H Properties of product Analysis, percentCalculated Found Example Solvent used Yield Number ml.) (g.) C H N C H NM.P. 0.)

As OnHuNaOa 2 Ethanol (80)...- 8. 3 57.81 7. 2B 25. 28 57.92 7. 26.25.00 87-88 (llgroln).

AS C1|H1|N|O| 3 Ethanol (30) 3. 4 54. 84 7. 4B 23. 98 84. 96 7. 59 24.15 114-115 (ethyl-acetate).

As CaoHuClNflJr 4. Ethanol (70) 7. 3 57. 61 6. 04 20.16 57. B 6.06 20.19 152-1525 (ethanol).

AS C1IH2|N|O| ll Ethanol (70)..-- 8.1 54. 84 7. 4B 23. 98 64. 69 7. 4423. 85 80-82 (ethybaeetete) Th. denotes theophylllne ring.

EXAMPLE 6 EXAMPLE 8 To a mixture of 7.2 g. of7-(fl-bromoethyl)-theophylline and 9.5 g. phenylethylpiperazine wasadded 70 ml. of ethanol. The mixture was treated in the same manner asin Example 1 to give 10.5 g. of crude 7-[fl-(N phenyl-ethylpiperadinoethyl] -theophylline. This crude product was dissolved in 50 ml. ofabsolute ethanol and to this solution absolute ethanol containingcalculated amount of hydrogen chloride was added. The precipitate formedwas collected by filtration to give g. of 7-[18- (Nphenylethylpiperazino)-ethyl]-theophylline hydrochloride, which uponrecrystallization from 80% ethanol decomposes at 264266 C.

Elemental analysis-Cale. as C H N O 'ZHCI (percent): C, 53.73; H, 6.44;N, 17.90. Found (percent): C, 53.71; H, 6.38; N, 17.98.

EXAMPLE 7 6.5 g. of 7-( -chloropropy1)-theophylline and 6.4 g. ofpropylpiperazine were dissolved in 70 ml. of ethanol. The solution wastreated in the same manner as in EX- ample 1 to give 8.4 g. of7-['y-(N-propylpiperazino)- propyl]-theophylline which recrystallizesfrom isopropyl ether. M.P. 72-73 C.

Elemental analysis-Cale as C -;H N O (percent): C, 58.59; H, 8.10; N,24.12. Found (percent): C, 58.21; H, 7.98; N, 23.96.

1.0 g. of 7-[y-(Nflpropylpiperazino)-propyl]-theophylline thus obtainedwas dissolved in 5 ml. of absolute ethanol. To this solution, absoluteethanol containing calculated amount of hydrogen chloride was added. Theprecipitate was collected by filtration to give 1.0 g. of thecorresponding hydrochloride which upon recrystallization from 90%ethanol, decomposes at 302303 C.

Elemental analysis.-Calc. as C H N O -ZHCl (percent): C, 48.45; H, 4.18;N, 19.94. Found (percent): C, 48.30; H, 4.36; N, 20.31.

10 g. of 7-( -bromopropyl)-theophylline and 5.3 g. of benzylpiperazinewere dissolved in 30 ml. of ethanol. The solution was treated in thesame manner as in Example 6 to give 12.6 g. of 7-[ -(N-benzylpiperazino)propyl1- theophylline hydrochloride which uponrecrystallization from ethanol decomposes at 284-285 C.

Elemental analysis.Calc. as C21H23NflO2'2HCl (percent): C, 53.73; H,6.44; N, 17.90. Found (percent): C, 53.52; H, 6.72; N, 17.61.

EXAMPLE 9 EXAMPLE 10 A solution of 7.2 g. of 7-fI-brornoethyl)-theophylline, 5.5 g. of m-chlorobenzylpiperazine and 2.6g. of triethylamine in 70 ml. of ethanol was subjected to reflux for 6hours under heating and stirring. After cooling the refiuxed solutionwas concentrated under reduced pressure. The residue was washed withwater and recrystallized from ethanol to give 8.4 g. of 7-[fl-{N-(m-chlorobenzyl)- piperazino}-ethyl]-theophylline.

Elemental analysis.--Calc. as C H ClN O (percent): C, 57.61; H, 6.04; N,20.16. Found (percent): C, 57.52; H, 6.13; N, 20.31.

7 EXAMPLE 11 1.8 g. of theophylline was added to a solution of 0.4 g. ofcaustic soda in 20 ml. of ethanol. To the mixture, a solution of 2.5 g.of N -benzyl-N -('y-chloropropyl)pisoluble matter was removed byfiltration and the mother liquor was concentrated to dryness. The driedprodfict'wa's recrystallized from ethanol to give 12 g. of7-[,6-hydroxy- -{N -(p chlorobenzyl) piperazino}-propyl]-theophyhline.M.P. 150-l51 C. 1 perazine 1n 5 ml. of ethanol was dropped duringminutes under boiling and stirring and further refluxed for Elemef'ml hi21 n7 lNsO (percent); 7 hours under heating. After cooling insolublematter Found (Percmn' 5631' was removed by filtration. The filtrate wasconcentrated and the residue was dissolved in 10 ml. of absolute EXAMPLE14 ethanol. The solution was treated in the same manner as 10 A solutionof 7.2 of potassium theophylline and 10 g. of in Example 6 to give 3.0g. of 7-['y-(N -benaylpipera- N -(p-chlorobenzyh-N -(p-hydroxy 'ychloropropyl)- zino)-propyl]-theorphylline hydrochloride which uponpiperazine i 30 m1, of th l was bj t d t flu recrystallization from 80%methanol decomp ses a under heating for 8 hours. After removal ofinsoluble 283284.S C. matter in warm state by filtration, the motherliquor was Elemental ana1ysls.-Calc. as CZ1H28OGNB'ZHCI (P 15concentrated to dryness. The dried product was recrystalcentr C. 1 u d(p lizled from ethanol to give 11.0 g. of 7-[fl-hydroxy- -(N 53.49; H,6.53; N, 17.71. (p chlorobenzyl) piperazino} propylytheophyllinel M.P.150151 C. 1 EXAMPLE 12 90 Elemental analysis.-Calc. as c H37C1N5O(percent): 3.0 g. of theophylline was added to a solution of 0.6 g. C,H, Found (P 55.52; of caustic soda in 30 ml. of ethanol. To the mixtureunder H, 615; N, 19.00. reflux with heating, a solution of 3.6 g. of N-benzyl N EXAMPLE 15 8-chloroethyl)-piperazine in 10 ml. of ethanol was5 3 g f h lli nd 6 5 g of N -fl 'y'epoxy l P Y dropped during 15 minutesand sub ected to reflux under NLbutylpiperazine were added to 50 mLQfisopmppfiol heating 7 hours- After 0011115 and removal of and caused toreact under heating on a water bath for soluble matter the mother liquorwas concentrated to 5 hours Afigr cooling, crystals depositednwereccnected Y P The produci'vas l from ethanol by filtration andrecrystallized from ethyl acetate to give to ey 5 of 3 1benlylplveralmel-elhyll'lhw 8.0 g. of 7-[B-hydroxyy-(N-butylpiperazino)-propyl]- p y 120 C. theophylline. MP. 146-147 c.

Elememal analymcalcas cflvHflfiNdofl (Percenn' Elemental analysis.Calc.as c H NqO (percent): 2 2 g-2; N, Found (WCWP 62-87; c, 57.12; H, 7.99;N, 22.20. Found (percent):'C, 57.09;

1 g. of 7-[p-(N benzylpiperadino)-ethyl]-tl1eophylline 04 N 22 7 EXAMPLE16 p thus obtained was treated in the same manner as in Example 7 togive 1.1 g. of the corresponding hydrochloride P B Y' P YP PY p y and B-which was recrystallized from 90% methanol and decomof ethylplperazmewere afided to 43 1111- Of ethanol a d posed at 275 Q caused to reactunder heating on a water bath for 5 hours.

Elemenm; c as C H N 0 .2HCl.H o rafter cooling, crystals deposited werecollected by filtra- (percent): C, 50.74; H, 6.39; N, 17.75. Found(percent); mm and recrystallized from ethanol acetic acid (4:1) C,50.81; H, 6.57; N, 17.67. solution to give 5 g. of 7-[fl-hydroxy-v-(N-ethylp1perazrno)-propyl]-theophyl11ne. M.P. 145-l45.5 C. I EXAMPLE 13Elemental analysis.Calc. as ClBHgflNgOg (percent):

A solution of 6.0 g. of theophylline, 10 g. of N -(pg f g-gg Found (pent): C, 55.16; chIorObenZyD-N -(fl-hydmxy 'y chloropropyl)-pipera-EXAMPLES 1742 zinc and 2.4 g. of anhydrous potassium carbonate in ml. ofethanol was subjected to reflux under heating and The following productswere obtained by the same manstirring for 8 hours. After completion ofthe reaction, inner as in Example 16.

TABLE 2 Reactants Eiiiiiiii: Product 'lh-A (g.) HN

17 7-[fl-hydroxy-Y-(N -al1yl- A: R:

piperazlno)-propyl)- thoophylline. CHrCH-CHz cmcn=cn, I

18 7-[fl-hydroxy-1 -{Nqfl- A: R:

hydro): yethyl) -plllperazino] propyll-theophy lne. CH;CH-GH; -CH;-CH1OH19 7-[B-hydroxy-7-(N -cl1loro- A: R:

benzyU-piperazino -propyl]- theophylline. CH -CH-CH Jun-@411 (4.7) (6.3)

20 7-[5-hydroxy-1-(N -phenyl- A:

ethylplperazlno)-propyl]- thcophyllinc.

TABLE 2.ontiuued Reactants Example H16 N-R (3-) Number Product 'Ih-A (g)21 7-[fl-hydroxyw-[N 4 -meth0xy- A: R;

henzyD- lperazino -propyl]- theophy llne. CH;CHCH;

\ OH OCH;

22 7-[B-hydroxy -1-iN -(p-isopropyl- A: B:

benzyD-piprazlnol -propyl] theophy line. -CHz-C Ii-/C Hi /OH Properties0! product Analysis percent Calculated Found Example Solvent used YieldNumber ml.) (g.) H N C H N M.P. 0.)

AS! CnHaNK); 17 Ethanol (50)-.-- 3.8 56.33 7.23 22.92 56.01 7. 33 23.19140.5-14L0 (ethanolacetic acid mixture).

AS: CuHuN O 18 Ethanol 4.5 52.44 7.15 22.04 52. 71 7.216 22,1541535-1545 (ethauoL acetic acid mixture).

AS: 021113 0151); 19 Ethanol 7.1 56.44 0.09 18.80 56.51 6.17 19.20 -151(ethanol).

A8; CM wN O; 20 Ethanol (200)..- 25.3 61.95 7.09 19. 70 01.87 7.12 19.87 1485-1495 (ethanol).

AS: cnflgobho 21 Ethanol 23.8 59. 71 0.83 18.99 59.34 0.71 18.99151.5152.5 (ethanol).

AS: C H MO; 22 Ethanol (200).-- 38.5 63.41 7.54 18.49 63.22 7.46 18.37177-178 (ethanol).

EXAMPLE 23 react with 4.2 g. of O-chlorobenzyl-piperazine at 70-80 4 g.of 7-(flgy-epoxypropyl)-theophylline was caused to C. for 5 hours understirring. After cooling, the reaction product was recrystallized frommethanol to give 6.5 g. of 7 [p hydroxy-y-{N(O-chlorobenzyl)-piperazino}- propylJ-theophylline. M.P. 169170 C.

Elemental analysis.Calc. as C21H21C1N5O3 (percent): C, 56.44; H, 6.09;N, 18.80. Found (percent): C, 56.48; H, 6.09; N, 19.17.

EXAMPLES 25-26 The following products were obtained by the same manneras in Example 24.

TABLE 3 Properties of product Reactauts Analysis, percent r/ CalculatedFound Ex. H N-B (g.) Yield 0 No. Product T11A(g.) (g.) C H N C H N M.P.(C.)

25"... 7- h d o N'- CH CH-CH Cl Aa:OnH:1C1N 0;

51.35125 Zm nr 14.3 55.44 5.09 18.80 55.53 5.99 15.54 rec-m5piperazlnol-propyll- (ethanol). theophyliine. (10.8) -CHg 26...T-[B-hydrox --v-IN- -OH1CH--CH1 As: CnHsuNaO (p-methy benzyD- -CHr- CH:24.5 61.95 7.09 19.70 62.11 7. 45 19.87 157-158 piperazinol-propyll- 0(ethanol) theophylliue. (18.6) (18) 1 1 EXAMPLE 27 A solution of 7.6 g.of 7-(fl-hydroxy-q-chloropropyl)4 1 theophylline and 7.8 g. ofpropylpip'eraz'ine' in70 m1. of

isopropanol was subjected to reflux for 7 hours under heating andstirring. After completion of the reaction, ethanol was distilled oil.The residue was dissolved in chloroform, washed with water and dried.chloroform was distilled off to give an oily substance. This oilysubstance. was added to 5.1 g. of7-(B-hydroxy-y-bromopropyl)-theophylline, 2.7 g. of-hydroxypropylpiperazine and 2.2 g. of anhydrous sodium carbonate wereadded to 40 ml. of ethanol. The mixture was subjected to reflux underheating and stirring for 6 hours. The insoluble matter was collected inwarm state by filtration and ethanol was distilled otf under reducedpressure. Recrystallization of the residue from ethanol gave 4 g. of7-[ti-hydroxy-y-{N (-y-hydroxypropyl) piperazino) propyl]theophylline.M.P. 164- 165 C.

Elemental analysis.Calc. as C H N O (percent): C, 53.67; H, 7.42; N,22.09. Found (percent): C, 53.56; H, 7.43; N, 22.27.

EXAMPLE 29 To a suspension of 4.4 g. of theophylline and 3.2 g. ofanhydrous potassium carbonate in 60 ml. of ethanol was added 5.4 g. of N(fihydroxy-qt-chloropropyl)-N*-butylpiperazine which was obtained byreacting 4.6 g. of butylpiperazine with 3 g. of epichlorohydrin in 80ml. of ethanol at 30 C. for 3 hours. The mixture was treated in the samemanner as in Example 13 to give 6.4 g. of 7 [flhydroxy-w-(N-butylpiperazino)-propyl]-theophylline. M.P. l44.5-146.5 C.

Elemental anaIysis.-Calc. as C H N O (percent): C, 57.12; H, 7.99; N,22.20. Found (percent): C, 58.01; H, 7.76; N, 22.16.

EXAMPLE 30 16.3 g. of 7-(B-hydroxy-y-chloropropyl)-theophylline and 29.6g. of p-chlorobenzylpiperazine were added to 150 ml. of ethanol. Themixture was treated in the same manner as in Example 27 to give 21.2 g.of 7-[fi-hydroxy- -{N (p-chlorobenzyl -pipera zine} -propyl]-theophyl1ine. Recrystallize from ethanol. M.P. 150151 C.

Elemental analysis.Calc. as CmHgqClNgOg (percent): C, 56.44; H, 6.09; N,18.80. Found (percent): C, 56.23; H, 6.05; N, 18.91.

EXAMPLE 31 19 g. of 7-(fl-hydroxy-v-bromopropyl)-theophylline, 14.8 g.of m-chlorobenzylpiperazine and 7.1 g. of triethylamine were added to153 ml. of ethanol. The mixture was subjected to reflux under heatingand stirring for 6 hours. The residue, after distillation off of thesolvent, was washed with water and recrystallized from ethanol to give22.5 g. of 7-[p-hydroxy- -{N -(m-chlorobenzyD-piperazino}-propyl]-theophylline. M.P. 160.5-161" C.

Elemental analysis.Cale. as C H ClN O (percent): C, 56.44; H, 6.09; N,18.80. Found (percent): C, 56.31; H, 6.00; N, 18.65.

EXAMPLE 32 2.7 g. of 7-(fl-hydroxy-v-chloropropyl)-theophy1line, 2.2 g.of p-isopropylbenzylpiperazine and 1.1 g. of triethylamine were added to30 ml. of ethanol. The mixture was subjected to reflux under heating andstirring for 6 hours. After completion of the reaction and distillationoil of the solvent, the residue was washed with water and 12recrystallized from ethanol to give 3.5 g. of 7-[fl-hydroxyy- {N (pisopropylbenzyl)-piperazino} propyl]- theophylline. M.P. 1775-178 C.

Elemental analysis.-Calc. as c,,H,,N,o, (percent): C, 63.41; H, 7.54; N,18.49. Found (percent): C, 63.35;

EXAMPLE 33 23 g. of 7-(fi-hydroxy-y-chloropropylI-theophylline and 34.1g. of phenylethylpiperazine were added to 200 ml. of ethanol. Themixture was treated in the same manner as in Example 27 to give 25.3 g.of 7-[B-hydroxy-7- (N phenylethylpiperazino)-propyl]-the0phylline. M.P.147149" C.

Elemental analysis.-Calc. as CggHggNgOg (percent): C, 61.95; H, 7.09; N,19.70. Found (percent): C, 61.72; H, 6.88; N, 20.03.

EXAMPLE 34 10.6 g. of 7-(fl-hydroxy-v-chloropropyl)-theophy1line, 7.2 g.of o-chlorobenzylpiperazine and 2.8 g. ,of anhydrous potassium carbonatewere added to 100 ml. of ethanol. The mixture was treated in the samemanner as in Example 13 to give 14.2 g. of 7-[p-hydroxy-v-{N-(ochlorobenzyl) piperazine} propyl] theophylline. M.P. 169-170 c.

Elemental analysis.-Calc. as C H ClN O (percent): C, 56.44; H, 6.09; N,18.80. Found (percent): C; 5&34; H, 6.14; N, 18.85.

EXAMPLE 35 5 g. of 7-(fi,' -epoxypropyl)-theophylline and 5 g. of anaphthylmethylpiperazine were added to 50 ml. of ethanol and caused toreact for 5 hours on a water bath. Removal of the solvent bydistillation gave 9 g. of 7-[B- hydroxy 'y-{N-(d-naphthylmethyl)-piperazino}-propyl]- theophylline which wasdissolved in a small amount of absolute ethanol. To the solution,absolute ethanol containing calculated amount hydrogen chloride wasadded and the precipitate formed was collected by filtration to give 9.5g. of 7[fl-hydroxy-v-{N-(a-naphthylmethynpiperadino}-propyl]-theophylline which uponrecrystallization from ethanol decomposes at 272-274 C.

Elemental analyst'.r.Calc. as C H N O -2HCl (percent): C, 56.07; H,6.02; N, 15.69. Found (percent): C, 55.91; H, 6.28; N, 15.34.

EXAMPLE 3 6 6.3 g. of 7-(p-hydroxy- -chloropropyl)-theophylline and 8.9g. of a-naphthylmethylpiperazine were subjected to reflux in 70 ml. ofethanol under heating, for 6 hours. After completion of the reaction andremoval of ethanol by distillation, the residue was dissolved inchloroform, washed with water and dried. Removal of chloroform bydistillation gave 7.4 g. of crude 7-[B-hydroxy- -{N -(anaphthylmethyl)piperazino}-propyl]-theophylline. The crude product was dissolved in asmall amount of ethanol and treated in the same manner as in Example 35to give 7.8 g. of 7-[fi-hydroxy- -{N-(e-naphthylmethyl)-piperazino}-propyl]-theophylline hydrochloride whichupon recrystallization from 80% ethanol decomposes at 273 274 C.

Elemental analysis.-Calc. as C H N O '2HCl (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 55.98; H, 6.01; N, 15.82.

EXAMPLE 37 2.2 g. of potassium theophylline and 3.2 g. of N -(flhydroxy7 chloropropyl) N*-(a-naphthylmethy1)- piperazine were subjected toreflux in 30 ml. of ethanol for 8 hours under heating. After removal ofinsoluble matter, the mother liquor was concentrated to dryness to give4.2 g. of crude 7-[fl-hydroxy-y-{N (m-naphthylmethyl) piperazino}propyl]-theophylline. This crude product was dissolved in a small amountof absolute ethanol and treated in the same manner as in Example 35 togive 3.3 g. of 7-[p-hydroxyw-{N (a-naphthyl- 13 methyl) piperazino}propyl]-theophylline hydrochloride which upon recrystallization from 80%ethanol decomposes at 271-273 C.

Elemental analysis.Calc. as C H N O -2HCl (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 56.03; H, 5.97; N, 15.54.

EXAMPLE 38 6.8 g. of 7-(B-hydroxy-y-chloropropyl)-theophy1line, 6.3 g.of u-naphthylmethylpiperazine and 2.7 g. of triethylamine were subjectedto reflux in 70 ml. of ethanol for 8 hours under heating. After removalof the solvent, the residue was dissolved in chloroform, washed withwater and concentrated to dryness to give 11.2 g. of crude 7 [,3 hydroxy'y {-(a-napthylmethyl)piperazino}- propyl]-theophylline. This crudeproduct was dissolved in a small amount of absolute ethanol and treatedin the same manner as in Example 35 to give 11.6 g. of 7-[5- hydroxy 'y{N (or naphthylmethyl)-piperazino}- propylJ-theophylline hydrochloridewhich upon recrystallization from 80% ethanol decomposes at 272274.5 C.

Elemental analysis-Cale. as C H N O -2HCl (percent): C, 56.07; H, 6.02;N, 15.67. Found (percent): C, 56.15; H, 5.79; N, 15.82.

EXAMPLE 39 10 g. of 7-(B-hydroxy-y-chloropropyl)-theophylline, 9 g. ofa-naphthylrnethylpiperazine and 3 g. of anhydrous potassium carbonatewere subjected to reflux in 100 ml. of ethanol under heating andstirring. After removal of insoluble matter, the mother liquor wasconcentrated to dryness to give 15.8 g. of crude 7-[B-hydroxy-y-{N-(anaphthylmethyl) piperazino} propyl] theophylline. This crude productwas dissolved in a small amount of absolute ethanol and treated in thesame manner as in Example 35 to give 16.4 g. of 7-[B-hydroxy- -{N-(otnaphthylmethyl)-piperazino}-propyl]-theophylline hydrochloride whichwhen recrystallized from 80% ethanol decomposes at 272-274 C.

Elemental analysis.Calc. as CQ5H3QNQO32HC1 (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 56.15; H, 5.99; N, 15.82.

EXAMPLE 40 4 g. of 7-(5,- -epoxypropyl)-thephylline was caused to reactwith 3.9 g. of a-naphthylmethylpiperazine at 70-80 C. for hours understirring. After cooling, the sludgy reaction mixture was dissolved in asmall amount of absolute ethanol. To the solution absolute ethanolcontaining calculated amount of hydrogen chloride was added and theprecipitate formed was collected by filtration to give 4.6 g. of7-[5-hydroxy-y-{N -(a-naphthylmethyl) piperazino}-propyl]-theophyllinehydrochloride which when recrystallized from 80% ethanol decomposes at272.5-273.5 C.

Elemental analysis.-Calc. as C H N O -2HC1 (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 55.97; H, 6.13; N, 15.49.

EXAMPLE 41 5:7 g. theophylline and 8.5 g. of N -(B,'y-epo-xypropyl)- N-(e-naphthylmethyl)-piperazine were subjected to reflux in 60 ml. ofethanol for 5 hours under heating. After removal of the solvent, theresidue was treated in the same manner as in Example 40 to give 7.7 g.of 7-[B-hydroxy- 'y {N (a-naphthylmethyl)piperazino}-propyl]-theophylline hydrochloride which when recrystallizedfrom 80% ethanol decomposes at 271"-273 C.

Elemental analysis-Cale. as C H N O -2HCl (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 55.87; H, 6.24; N, 15.50.

EXAMPLE 42 15 g. of 7 (5 bromoethyl) theophylline, 8.3 g. ofethoxycarbonylpiperazine and 5.6 g. of triethylamine were 14 dissolvedin 150 ml. of ethanol and the solution was subjected to reflux underheating for 8 hours. After removal of the solvent by distillation theresidue was washed with water to give 16 g. of 7-[;3-(N-ethoxycarbonylpiperazino)- ethyl]-theophylline which is recrystallizedfrom ethanol. M.P. 135.5l37.5 C.

Elemental analysis.-Calc. as C H N Q, (percent): C, 52.73; H, 6.64; N,23.06. Found (percent): C, 52.43; H, 6.34; N, 23.18.

EXAMPLE 43 15 g. of 7 ()8 bromoethyl) theophylline, 8.3 g. ofethoxycarbonylpiperazine and 7.2 g. of anhydrous potassium carbonatewere subjected to reflux in 50 ml. of ethanol under heating for 8 hours.After removal of insoluble matter by filtration in warm state, thesolvent was distilled off to give 16.5 g. of 7-[fi-(N-ethoxycarbonylpiperazino)-ethyl]-theophylline which is recrystallizedfrom ethanol. M.P. 136l37 C.

Elemental analysis.Calc. as C H N O (percent): C, 52.73; H, 6.64; N,23.06. Found (percent): C, 52.55: H, 6.59; N, 22.98.

EXAMPLE 44 6 g. of theophylline was added to a solution of 1.2 g. ofcaustic soda in 60 ml. of ethanol and to the mixture, a solution of 7 g.of N -ethoxycarbonyl-N (p -chloroethyl)-piperazine in 10 ml. of ethanolwas dropped during 15 minutes under reflux with heating and stirring andfurther refluxed for 7 hours under heating. After cooling insolublematter was removed by filtration. The mother liquor was concentrated todryness and the residue was recrystallized from ethanol to give 4.8 g.of 7-[fi-(N ethoxycarbonylpiperazino) ethyl] theophylline. M.P.136.5-137 C.

Elemental analysis-Cale. as ClQIIQQNflO (percent): C, 52.73; H, 6.64; N,23.06. Found (percent): C, 52.68; H, 6.72; N, 23.10.

EXAMPLE 45 3.5 g. of 7-(fi-bromoethyl)-theophyl1ine and 3.4 g. ofacetylpiperazine were subjected to reflux in 5 ml. of ethanol underheating for 8 hours. After completion of the reaction and removal of thesolvent, the residue was dissolved in chloroform and washed with waterand dried. Chloroform was distilled off to give 3 g. of 7-[B-(Nacetylpiperazino)-ethyl]-theophylline which is recrystallized from ethylacetate. M.P. 140141 C.

Elemental analysis.Calc. as C, H N O (percent): C, 53.88; H, 6.63; N,25.14. Found (percent): C, 53.91; H, 6.52; N, 25.10.

EXAMPLE 46 5.5 g. of 7 (B-bromoethyl) theophylline, 3.6 g. ofbenzoylpiperazine and 1.9 g. of triethylamine were treated in 55 ml. ofethanol in the same manner as in Example 42 to give 1 g. of 7-[B-(N-benzoylpiperazino)-ethyl]- theophylline which is recrystallized fromethyl acetate. M.P. 184-185 C.

Elemental analysis.Calc. as 0,,H,,N,0, (percent): C, 60.59; H, 6.10; N,21.20. Found (percent): C, 60.58; H, 6.02; N, 20.99.

EXAMPLE 47 3.6 g. of potassium theophylline and 4.2 g. of N benzoyl-N-;8-chloroethyl-piperazine were subjected to reflux in 40 ml. of ethanolunder heating for 8 hours. After completion of the reaction, insolublematter was removed by filtration and the mother liquor was concentratedto dryness. The residue was recrystallized from ethyl acetate to give6.1 g. of 7-[ 9-(N' -benzoylpiperadino)-ethyl]- theophylline. M.P.184"185 C.

Elemental analysis-Cale. as C H N O (percent): C, 60.59; H, 6.10; N,21.20. Found (percent): C, 60.33; H, 6.21; N, 21.53.

15 EXAMPLE 4s 6 g. of 7-( 9-bromoethyl)-theophylline, 1.9 g. ofanhydrous piperazine and 2.3 g. of triethylamine were subjected toreflux in 60 ml. of ethanol under heating for 8 hours. After completionof the reaction and removal of the solvent by distillation, the residuewas dissolved in chloroform and insoluble matter was removed. Afterwashing with water and drying, chloroform was distilled off. The residuewas extracted with ethanol and the solvent was distilled oflf to give5.8 g. of crude 7-(t3-piperazinoethyl)-theophylline. This crude productwas dissolved in 20 ml. of absolute ethanol. To the solution ethanolsolution of equivalent amount of p-tolucne sulfonic acid was added andthe crystals deposited were collected by filtration to give 10.5 g. ofdiparatoluene sulfonate of 7-(fipiperadinoethyl) theophylline whichdecomposes at 223.5-224.5 C.

Elemental analysis.Calc. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 51.12; H, 5.64; N, 13.61.

EXAMPLE 49 4.4 g. of potassium theophylline and 3 g. offl-chloroethylpiperazine were subjected to reflux in 60 ml. of ethanolunder heating for 8 hours. After cooling, insoluble matter was filteredolf and the mother liquor was concentrated to give 5.3 g. of crude7-(fl-piperadinoethyl)- theophylline. This crude product was dissolvedin 20 ml. of absolute ethanol. To the solution, ethanol solution ofequivalent amount of p-toluene sulfonic acid was added and the crystalsdeposited were collected by filtration to give 10 g. of diparatoluenesulfonate of 7-(fl-piperazinoethyl)-theophylline which whenrecrystallized from ethanol decomposes at 222.5 "-224" C.

Elemental analysis-Cale. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 50.79; H, 5.55; N, 13.19.

EXAMPLE 50 23.6 g. of 7-(Bn-epoxypropyl)-theophylline and 19 g. ofethoxycarbonyl-piperazine were subjected to reflux in 230 ml. of ethanolunder heating for 3 hours. After cooling, crystals deposited werecollected by filtration to give 30.1 g. of 7-[fl-hydroxy- -(Nethoxycarbonylpiperazino)- propyl] -theophylline which is recrystallizedfrom ethanol. M.P. 178-179 C.

Elemental analysis-Cale. as C H N O (percent): C, 51.77; H, 6.64; N,21.31. Found (percent): C, 51.51; H, 6.63; N, 21.18.

EXAMPLE 51 3 g. of theophylline, 4.2. g. of N -ethoxycarbonyl-N(fl-hydroxy-y-chloropropyl)-piperazine and 1.2 g. of anhydrous potassiumcarbonate were subjected to reflux in 60 ml. of ethanol under heatingfor 8 hours. After completion of the reaction, the reaction solution wasfiltered and the mother liquor was concentrated under reduced pressure.The residue was recrystallized from ethanol to give 5.2 g. of7-[fl-hydroxy-y-(N -ethoxycarbonylpiperazino)-propyl]-theophylline. M.P.178-179 C.

Elemental analysis-Cale. as C11Hg6N (percent): C, 51.77; H, 6.64; N,21.31. Found (percent): C, 51.82; H, 6.58; N, 21.14.

EXAMPLE 52 7.1 g. of 7-(B,'y-epoxypropyl)-theophylline and 6.8 g. ofbenzoylpiperazine were subjected to reflux in 70 ml. of ethanol underheating for 6 hours. After cooling, crystals deposited were collected byfiltration to give 11.6 g. of 7 [,9 hydroxy-y-(N-benzoylpiperazino)-propyl]-theophylline which is recrystallized frombutanol. M.P. 155- 156 C.

Elemental analysis-Cale. as C I-1 N 0 (percent): C, 59.14; H, 6.15; N,19.71. Found (percent): C, 59.43; H, 6.46; N, 19.62.

16 EXAMPLE 53 5.1 g. of 7-(p-hydroxy-y-chloropropylj-theophylline, 4 g.of benzoylpiperazin and 1.4 g. of anhydrous potassium carbonate weresubjected to reflux in 60 ml. of ethanol under heating for 8 hours.After completion of reaction, insoluble matter was removed by filtrationin warm state and the mother liquor was concentrated. The residue wasrecrystallized from butanol to give 6.4 g. of 7-[fl-hydroxy- 'y-(N*-benzoylpiperazino) -propyl] -theophylline.

Elemental analysis.-Calc. as C l-1 N 0 (percent): C, 59.14; H, 6.15; N,19.71. Found (percent): C, 59.30; H, 6.23; N, 19.84.

EXAMPLE 54 4.3 g. of potassium theophylline and 5.6 g. of N benzoyl N-(fi-hydroxyy-chloropropyl)-piperazine were subjected to reflux in ml.of ethanol under heating for 8 hours. After completion of the reaction,insoluble matter was removed by filtration and the mother liquor wasconcentrated. The residue was recrystallized from butanol to give 5.2 g.of 7-[fi-hydroxy-y-(N -benzoylpiperazino)- propylJ-theophylline. M.P.154155 C.

Elemental analysis.-Calc. as C l-1 N 0 (percent): C, 59.14; H, 6.15; N,19.71. Found (percent): C, 59.28; H, 6.10; N, 19.87.

EXAMPLE 55 1.8 g. of theophylline and 2.5 g. of N -benzoyl-N(flyy-epoxypropyU-piperazine were subjected to reflux in 20 ml. ofethanol under heating for 7 hours. After completion of reaction, thesolvent was removed by distillation under reduced pressure. The residuewas recrystallized from ethanol to give 2.8 g. of 7-[fl-hydroxy'v'lN-bcnzoylpiperazino)-propyl]-theophylline. M.P. 154155 C.

Elemental analysis.Calc. as C, H, N 0 (percent): C, 59.14; H, 6.15; N,19.71. Found (percent): C, 59.02; H, 6.36; N, 19.68.

EXAMPLE 56 9 g. of 7-(fi,'y-epoxypropyl)-theophylline and 5.4 g. ofacetylpiperazine were subjected to reflux in 100 ml. of ethanol underheating for 7 hours. After completion of the reaction, the solvent wasdistilled 01f. The residue was recrystallized from ethanol to give 10 g.of 7-[B-hydroxy- -(N acetylpiperazino) propyl] thiophylline. M.P.l74.5176.5 C.

Elemental analysis-Cale. as C H N O, (percent): C, 52.75; H, 6.64; N,23.06. Found (percent): C, 52.51; H, 6.4-0; N, 22.89.

EXAMPLE 57 9.8 g. of 7-(p,'y-epoxypropyl)-theophylline and 5.2 g. offormylpiperazine were subjected to reflux in 100 ml. of ethanol underheating for 6 hours. After completion of the reaction, the solvent wasdistilled off. The residue was recrystallized from ethanol to give 10 g.of 7-[B-hydr0xy- *y-(N formylpiperazino) propyl] theophylline. M.P. l10l1 1 C.

Elemental analysis-Cale. as C H N O (percent): C, 51.42; H, 6.33; N,23.99. Found (percent): C, 51.27; H, 6.20; N, 24.10.

1 7 EXAMPLE 59 3.8 g. of 7-(B,'y-epoxypropyl)-theophylline and 3.1 g. of'benzoylpiperazine were reacted at 7080 C. for 5 hours under stirring.After cooling, the reaction product was recrystallized from ethanol togive 5.8 g. of 7-[ 8- hydroxy- -(N* benzoylpiperazino) propyl]theophylline. M.P. 154-156 C.

Elemental analysis-Cale. as C H N O (percent): C, 59.14; H, 6.15; N,19.71. Found (percent): C, 59.08; H, 6.23; N, 19.59.

EXAMPLE 60 A solution of g. of 7-(fl,'y-epoxypropyl)-thcophylline in 150ml. of ethanol was dropped, under stirring and refluxing, into 66 ml. ofethanol solution of 16 g. of piperazine hexahydrate during 2 hours andthe reflux was continued further for 5 hours. After cooling insolublematter was filtered off and the solvent of the mother liquor wasdistilled off under reduced pressure to give 11 g. of crude7-(fl-hydroxy- -piperazinopropyl)-theophylline. This crude product wasdissolved in 10 ml. of ethanol. To the solution, ethanol solution ofequivalent amount of p-toluenesulfonic acid was added to givedip-toluenesulfonate of 7-(fi-hydroxy-w-piperazinopropyl)- theophyllinequantitatively which is recrystallized from ethanol and decomposes at250.5 -25l.5 C.

Elemental analysis.-Calc. as C H N O S (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.52; H, 5.75; N, 12.49.

EXAMPLE 61 19.8 g. of theophylline, 17.9 g. of fl-hydroxy--chloropropyl-piperazine and 1 g. of anhydrous potassium carbonate weresubjected to reflux in 30 ml. of ethanol under heating for 8 hours.After completion of the reaction, insoluble matter was filtered off andthe mother liquor was concentrated to give 32 g. of crude 7-9-hydroxy-v-piperazinopropyl)-theophylline. This crude product wasdissolved in 35 ml. of ethanol. To the solution, ethanol solution ofequivalent amount of p-toluene sulfonic acid was added to givedi-p-toluene-sulfonate of 7- (fl-hydrozy-v-piperazinopropyl)theophylline quantitatively which when recrystallized from ethanoldecomposes at 250251 C.

Elemental analysis-(Talc. as C H N O S (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.52; H, 5.68; N, 12.60.

EXAMPLE 62 3.4 g. of 7-(fiq-epOxypropyl)-theophylline and 3.5 g. ofp-toluenesulfonylpiperazine were added to 40 ml. of ethanol andsubjected to reflux under heating for 7 hours. After cooling, thecalculated amount of p-toluenesulfonic acid was added and heated.Crystals deposited was collected by filtration to give 8 g. of dip-toluenesulfonate of 7 [fl hydroxy 7 (N ptoluenesulfonylpiperazino)-propyl]-theophylline which whenrecrystallized from ethanol decomposes at 162-163 C.

Elemental analysis.--Calc. as C H N O S (percent): C, 51.20; H, 5.40; N,10.24; Found (percent): C, 50.99; H, 5.51; N, 10.22.

EXAMPLE 63 4.7 g. of 7-[ 9-(N -ethoxycarbonylpiperazino)-ethyl]-theophylline obtained in Example 42 was dissolved in 47 ml. of cone.hydrochloric acid. The solution was subjected to reflux under heatingfor hours to hydrolyse. After completion of the reaction, the residuewas suspended in 50 ml. of absolute ethanol and into the solutionammonia gas was introduced. After removal of ammonium chloride produced,to the mother liquor was added ethanol solution of equivalent amount ofp-toluenesulfonic acid. Crystals deposited were collected by filtrationto give 5 g. of di-p-toluenesulfonate of7-(fipiperazinoethyl)-theophylline which when recrystallized fromethanol decomposes at 223 -224 C.

18 Elemental analysis-Cale. as C H N O S (percent): C, 50.93; H, 5.70;N, 13.20. Found (percent): C, 50.61; H, 5.53; N, 13.23.

EXAMPLE 64 To 2 g. of 7-[ 8-(N -ethoxycarbonylpiperazino)-ethyl]-theophylline produced in Example 42, 20 ml. of 35% hydrogenbromide-acetic acid solution was added with stirring and heated at 60 C.for 3 hours to conduct reaction. After cooling, deposited and solidifiedproduct was obtained by filtration and suspended in 20 ml. of absoluteethanol. Ammonia gas was introduced into the suspension and ammoniumchloride thus precipitated was removed by filtration. To the motherliquor, ethanol solution of equivalent amount of p-toluenesulfonic acidwas added. Crystals thus deposited were collected by filtration to give2.1 g. of di-p-toluenesulfonate of 7-(5- piperazino-ethyl)-theophyllinewhich when recrystallized from ethanol decomposes at 223 224.5 C.

Elemental analysis.-Calc. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 50.61; H, 5.53; N, 13.23.

EXAMPLE 65 2 g. of 7-[,8-(N -acetylpiperazino)-ethyl]-theophyllineobtained in Example 45 was dissolved in 20 ml. of conc. hydrochloricacid and treated in the same manner as in Example 63 to give 2.1 g. ofdi-p-toluenesulfonate of 7-[,fl-piperazinoethyl]-theophylline which whenrecrystallized from ethanol decomposes at 223.5-224 C.

Elemental analysis.Calc. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 50.82; H, 5.62; N, 13.21.

EXAMPLE 66 2 g. of 7-[B-(N benzoylpiperazino)-ethyl]-theophyllineproduced in Example 46 was dissolved in 20 ml. of cone. hydrochloricacid and was subjected to reflux under heating for 15 hours tohydrolyse. After cooling, benzoic acid thus deposited was filtered offand the mother liquor was concentrated under reduced pressure todryness. The residue was suspended in absolute ethanol and ammoniumchloride deposited by introducing ammonia gas into the suspension wasremoved by filtration. To the mother liquor, ethanol solution ofequivalent amount of p-toluenesulfonic acid was added, to give 2 g. ofdi-p-toluenesulfonate of 7-(p-piperazinoethyl)-theophy1line which whenrecrystallized from ethanol decomposes at 223- 224 C.

Elemental analysis.Calc. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 50.82; H, 5.62; N, 13.21.

EXAMPLE 67 2 g. of 7-[5-(N -formylpiperazino)-ethyl]-theophylline wassubjected to reflux in 10% caustic soda solution under heating for 3hours to hydrolyse. After cooling, the reaction product was subjected tosalting out with glanular caustic soda and extracted with chloroform.After removal of chloroform by distillation, the residue was dissolvedin 10 ml. of absolute ethanol. To the solution, ethanol solution ofequivalent amount of p-toluenesulfonic acid was added. Crystals thusdeposited were collected by filtration to give 2 g. ofdi-p-toluenesulfonate of 7-(p-piperazinoethyl)-theophylline which whenrecrystallized from ethanol decomposes at 223 224 C.

Elemental anaIysis.Calc. as C H N O S (percent): C, 50.93; H, 5.70; N,13.20. Found (percent): C, 50.85; H, 5.67; N, 13.33.

EXAMPLE 68 5 g. of 7-[fl-hydroxy-y-(N -ethoxycarbonylpiperazino)-propyl]-theophylline produced in Example 50 was dissolved in 50 ml. ofcone. hydrochloric acid and treated in the same manner as in Example 63to give 7.5 g. of di-p-tolnenesulfonate of7-(,B-hydroxy-y-piperazinopropyl)-theophylline which when recrystallizedfrom ethanol decomposes at 250-251 C.

19 Elemental analysis.Calc. as C H N O S (percent): C, 50.43; H, 5.74;N, 12.63. Found (percent): C, 50.48; H, 5.70; N, 12.63.

EXAMPLE 69 20 ml. of 35% hydrogen bromide-acetic acid solution was addedwith stirring to 2 g. of 7-[5-hydroxy-- -(N- ethoxycarbonylpiperazino-propy1] -theophylline produced in Example 50 and treated in the samemanner as in Example 64 to give 3.1 g. of di-p-toluenesulfonate of 7(fl-hydroxy-v-piperazino-propyl)-theophylline which when recrystallizedfrom ethanol decomposes at 249.5"- 250.5 C.

Elemental anaIysis.Calc. as C H N O S (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.25; H, 5.64; N, 12.57.

EXAMPLE 70 3.5 g. of 7-[Q-hYdI'OXY-'Y-(N -bCHZDYIPlPCTaZlHO)-PI'O-py1]-theophylline produced in Example 52 was dissolved in 35 m1. ofcone. hydrochloric acid and subjected to reflux under heating for 15hours. After cooling, benzoic acid deposited was removed by filtrationand also trace of benmic acid was extracted from the mother liquor withether. The mother liquor was concentrated under reduced pressure todryness and then treated in the same manner as in Example 68 to give 4.8g. of di-p-toluenesulfonate of7-[,B-hydroxy-q-(piperazino)-propyl]-theophylline which whenrecrystallized from ethanol decomposes at 249.5 -250.5 C.

Elemental analysis.Calc. as C l-1 14 8 (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.38; H, 5.55; N, 12.71.

EXAMPLE 71 A solution of 2 g. of 7-[fi-hydroxy- -(N-acetylpiperazino)-propyl]-theophylline produced in Example 56 in 20 ml.of cone. hydrochloric acid was subjected to reflux under heating for 15hours. After completion of the reaction, the solvent was distilled offand the residual solid matter was suspended in absolute ethanol.Ammonium chloride deposited by introducing ammonia gas into thesuspension was removed by filtration and the mother liquor wasconcentrated to give 1.5 g. of crude 7-[8-hydroxy-'y-piperazino-propyl]-theophylline. The crude product wasdissolved in 5 ml. of ethanol and to the solution, ethanol solution ofequivalent amount of ptoluenesulfonic acid was added to give 2.8 g. of7-[5- hydroxy-y-piperazinopropyl]-theophylline which when recrystallizedfrom ethanol decomposes at 250-251 C.

Elemental anaIysis.-Calc. as C H N O S (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.43; H, 5.68; N, 12.72.

EXAMPLE 72 5.6 g. of 7-[fi-hydroxy-v-(N'-formylpiperazino)-propyll-theophylline produced in Example 58 wassubjected to refiux in 60 m1. of cone. hydrochloric acid under heatingfor 15 hours to hydrolyse and treated in the same manner as in Example71 to give 0.7 g. of di-ptoluenesulfonate of 7(B-hydroxy-y-piperazinopropyl)- theophylline which decomposes at 249.5-250.5 C.

Elemental analysis.Calc. as C- H N O S (percent): C, 50.43; H, 5.74; N,12.63. Found (percent): C, 50.24; H, 5.82; N, 12.71.

EXAMPLE 73 9.4 g. of 7-[fi-(N -ethoxycarbony1piperazino)-ethyl]-theophylline was added to 94 ml. of cone. hydrochloric acid and heatedto hydrolyse. 4.4 g. of the crude 7-(flpiperazinoethyl)-theophyllinethus obtained, 2.5 g. of pchlorobenzylchloride and 1.6 g. oftriethylamine were added to 50 ml. of ethanol and the mixture wassubjected to reflux under heating for 8 hours. After completion of thereaction, the solvent was distilled off and the residue was washed withwater, recrystallized from 20 ethanol to give 5 g. of 7-[;8-(N-p-chlorobenzylpiperazino)-ethyl]-theophy1line. M.P. 151.5152.5C.

Elemental anaIysis.Calc. as C H C1N O (percent): C, 57.61; H, 6.04; N,20.16. Found (percent): C, 57.55; H, 6.02; N, 20.20.

EXAMPLE 74 6.4 g. of7-(fl-piperazinoethyl)-theophylline-di-p-toluenesulfonate was suspendedin 64 ml. of ethanol. Ammonia gas was introduced into the suspension toobtain a free base. Ammonium sulfonate formed was removed by filtration.To the mother liquor, 1.7 g. of p-chloro benzylchloride and 2.1 g. ofanhydrous potassium carbonate were added and subjected to reflux underheating for 8 hours. Insoluble matter was removed by filtration and themother liquor was concentrated to give 3.8 g. of 7-[fi-{N-(p-chlorobenzyl)-piperazino}-ethyl] theophylline which wasrecrystallized from ethanol. M.P. l52l53 C.

Elemental analysis.Calc. as C H CIN O (percent): C, 57.61; H, 6.04; N,20.16. Found (percent): C, 57.63; H, 6.06; N, 20.15.

EXAMPLE 75 4.7 g. of 7-[fl-(N -ethoxycarbonylpiperazino)-ethy1]-theophylline was added to 47 ml. of cone. hydrochloric acid and heatedto hydrolyse. 2.2 g. of the crude 7-flpiperazinoethyltheophylline thusobtained, 1.1 g. of butylbromide and 0.8 g. of triethylamine were added25 ml. of ethanol and treated in the same manner as in Example 73 togive 2.1 g. of 7-[,8-(N -butylpiperazino)-ethyl]- theophylline which wasrecrystallized from ligroin. M.P. 78-79 C.

Elemental analysis.Calc. as C H N O (percent): C, 58.60; H, 8.10; N,24.12. Found (percent): C, 58.80; H, 8.05; N, 24.23.

EXAMPLE 76 4 g. of 7-[,8-(N -ethoxycarbonylpiperazino)-ethyl]-theophylline was added to 40 ml. of cone. hydrochloric acid and heatedto hydrolyze. 1.8 g. of the crude 7-(;8- piperazino-ethyl)-theophyllinethus obtained, 0.6 g. of trimethylenechlorohydrine and 0.5 g. ofanhydrous potassium carbonate were added to 20 ml. of ethanol andtreated in the same manner as in Example 74 to give 2 g. of 7 [fi-{N-(hydroxypropyl)-piperazino}-ethyl]- theophylline which wasrecrystallized from ethanol. M.P. 163-164 C.

Elemental analysis.Calc. as C H N O (percent): C, 53.67; H, 7.42; N,22.09. Found (percent): C, 53.60; H, 7.48; N, 22.07.

EXAMPLE 77 5 g. of 7 [fi-(N -ethoxycarbonylpiperazino)ethyl]-theophylline was added to 20 g. of 5% hydrogen bromideglacial aceticacid solution and heated at 60 C. to bydrolyze. 2.4 g. of the crude7-(B-piperazino-ethyl)-theophylline thus obtained, 1.4 g. ofo-chlorobenzylchloride and 0.6 g. of anhydrous potassium carbonate wereadded to 30 ml. of ethanol and treated in the same manner as in Example74 to give 2.7 g. of 7- [fi-{N-(o-chlorobenzyl)-piperazino}-ethyl]-theophylline which wasrecrystallized from ethanol. M.P. 159-160 C.

Elemental analysis.-Calc. as C H ClN O (percent): C, 57.61; H, 6.04; N,20.16. Found (percent): C, 57.63; H, 6.00; N, 20.15.

EXAMPLE 78 10 g. of 7-[fi-(N' acetylpiperazino)-ethyl]-theophylline wasadded to ml. of cone. hydrochloric acid and heated to hydrolyse. 4.8 g.of the crude 7-(B-piperazinoethyl)-theophylline thus obtained, 2.1 g. ofbenzylchloride, and 1.7 g. of triethylamine were added to 50 ml. ofethanol and treated in the same manner as in Example 73 to give 5.4 g.of 7-[/3-(N -benzylpiperazino)-ethyl]-theophylline which wasrecrystallized from ethanol. M.P. l20-12l C.

Elemental analysis.-Calc. as C H N O (percent): C, 62.81; H, 6.85; N,21.97. Found (percent): C, 62.74; H, 6.90; N, 22.01.

1 g. of 7-[B (Nbenzylpiperazino)-ethyl]-theophylline thus obtained wasdissolved in ml. of absolute ethanol and to the solution absoluteethanol containing calculated amount of hydrogen chloride was added. Theprecipitate formed was collected by filtration to give 1 g. of 7-[l3- (N-benzylpiperazino)-ethyl]-theophylline di hydrochloride which uponrecrystallization from 90% ethanol decomposes at 27 5-276 C.

Elemental analysis.-Calc. as C H N O -2HChH O (percent): C, 50.74; H,6.39; N, 17.75. Found (percent): C, 50.85; H, 6.32; N, 17.82.

EXAMPLE 79 4.7 g. of crude 7-(p-piperazinoethyl)-theophylline, obtainedby hydrolyzing 7.2 g. of 7-[l3-(N -formylpiperazino)-ethyl]-theophyllinewith 80 ml. of caustic soda, was dissolved in 5 ml. of methanol. Intothe solution under reflux with heating, 0.8 g. of ethylene oxide wasintroduced during 2 hours and further continued the reflux for 30minutes. The solvent was distilled off to give 3.8 g. of crude 7-[ti-{N-(B-hydroxyethyl)-piperazino}- ethyll-theophylline which was dissolvedin 20 ml. of absolute ethanol and to the solution absolute ethanolcontaining calculated amount .of hydrogen chloride was added. Theprecipitate thus formed was collected by filtration to give 6.9 g. of7-[B-{N -(B-hydroxyethyD- piperazinol -ethyl]-theophylline dihydrochloride which upon recrystallization from ethanol decomposes at268 269 C.

Elemental analysis.Calc. as C H N O -2HCl-H O (percent): C, 42.16; H,6.60; N, 19.66. Found (percent): C, 42.11; H, 6.62; N, 19.55.

EXAMPLE 80 10 g. of 7-[fl hydroxy-v-(N-ethoxycarbonylpiperazino)-propyl]-theophylline was hydrolyzed underheating at 80 C. with 40 g. of 32% hydrogen bromide-glacial acetic acid.7.8 g. of the crude 7-(/3-hydroxy-'y-piperazinopropyl)-theophylline thusobtained, 3.9 g. of p-chlorobenzyl chloride and 1.9 g. of anhydrouspotassium carbonate were added to 80 ml. of ethanol and treated in thesame manner as in Example 74 to give 9.4 g. of 7-[B-hydroxy- 'y{N (pchlorobenzyl piperazino}-propyl] -theophylline which was recrystallizedfrom ethanol. M.P. 150-151 C.

Elemental analysis.-Calc. as C H ClN O (percent): C, 56.44; H, 6.09; N,18.80. Found (percent): C, 56.58; H, 6.00; N, 19.12.

EXAMPLE 81 5 g. of 7 [B hydroxy-y-(N'-ethoxycarbonylpiperazino)-propyl]-theophylline was hydrolyzed underheating with 50 ml. of conc. hydrochloric acid. 4.1 g. of the crude7-(5-hydroxy 'y piperazino-propyl)theophylline thus obtained, 2.1 g. ofp-isopropylbenzyl chloride and 1.3 g. of triethylamine were added to 50ml. of ethanol and treated in the same manner as in Example 73 to give4.6 g. of 7-[ti-hydroxy-y-{N(p-isopropylbenzyl)-piperazino}-propyl]-theophylline which wasrecrystallized from ethanol. M.P. 177178 C.

Elemental analysis.Calc. as C H N O (percent): C, 63.41; H, 7.54; N,18.49. Found (percent): C, 63.25; H, 7.56; N, 18.50.

EXAMPLE 82 Into a suspension of 10 g. of 7-(fl-hydroxy--piperazino-propyl)-theophylline di-p-toluenesulfonate in 100 ml. ofethanol, ammonia gas was introduced to give free base. Ammoniumsulfonate thus formed was removed by filtration. To the mother liquor2.5 g. of o-chlorobenzyl chloride and 3.4 g. of anhydrous potassiumcarbonate were added and treated in the same manner as in Example 74 togive 5.4 g. of 7-[;8-hydroxy- -{N-(o-chlorobenzyl)-piperazino}-propyl]-theophylline which wasrecrystallized from ethanol. M.P. 170-17l C.

22 Elemental analysis.Calc. as C H ClN O (percent): C, 56.44; H, 6.09;N, 18.80. Found (percent): C, 56.52; H, 6.17; N, 18.94.

EXAMPLE 83 7 g. of 7-[B-hydroxy-y-(N -acetylpiperazino)-propyl]-theophylline was added to ml. of conc. hydrochloric acid and heated tohydrolyse. 4 g. of the crude7-(fi-hydroxy-v-piperazinopropyl)-theophylline thus obtained, 1.6 g. ofbenzylchloride and 1.3 g. of triethylamine were added to 50 ml. ofethanol and treated in the same manner as in Example 73 to give 4.1 g.of 7-[B-hydroxy- -(N -benzylpiperazino)-propyl]-theophylline which wasrecrystallized from ethanol. M.P. 175-l76 C.

Elemental analysis-Cale. as C H N O (percent): C, 61.14; H, 6.85; N,20.37. Found (percent): C, 61.37; H, 6.90; N, 20.68.

EXAMPLE 85 2 g. of 7-[B-hydroxy-y-(N -acetylpiperazino)-propyl]-theophylline was added to 20 ml. of cone. hydrochloric acid and heatedto hydrolyse. 1.5 g. of the crude7-(B-hydroxy-y-piperazinopropyl)-theophylline thus obtained, 0.7 g. ofbutyl bromide and 0.4 g. of anhydrous potassium carbonate were added to15 ml. of ethanol and treated in the same manner as in Example 74 togive 1.2 g. of 7-[B- hydroxy 'y (N-butylpiperazino)-propyl]-theophylline which was recrystallized fromethyl acetate. M.P. 146- Elemental analysis.-Calc. as C H N O (percent):C, 57.12; H, 7.99; N, 22.20. Found (percent): C, 57.08; H, 8.12; N,21.99.

EXAMPLE 86 In ml. of methanol was dissolved 6.7 g. of7-(B-hydroxy-y-piperazinopropyl -theophylline di-p-toluenesulfonate intowhich ammonia gas was introduced to allow conversion into free base andthe resulting ammonium sulfonate was filtered oil. To the filtrate 0.5g. of ethylene oxide was introduced and treated in the same manner as inExample 79 to give 2.7 g. of 7-[B-hydroxy- -{N hydroxyethyl) piperazino}propyl]-theophylline. M.P. 153 -154 C.

Elemental analysis.-Calc. as C H N O (percent): C, 52.44; H, 7.15; N,22.94. Found (percent): C, 52.65; H, 7.08; N, 23.01.

EXAMPLE 87 7 g. of 7-[fl-hydroxy-y-(N-benzoylpiperazino)-propylJ-theophylline was added to 100 ml. of conc.hydrochloric acid and heated to hydrolyse. 4.5 g. of 7-(fi-hydroxy--piperazinopropyl)-theophy1line thus obtained, 1.7 g. of allylbromideand 1 g. of anhydrous potassium carbonate were added to 50 m1. ofethanol and treated in the same manner as in Example 74 to give 3.5 g.of 7-[5- hydroxy 'y (N allylpiperazino)-propyl]-theophylline which wasrecrystallized from ethanol. M.P. -141 C.

Elemental analysis.-Calc. as C H N O (percent): C, 56.33; H, 7.23; N,22.92. Found (percent): C, 56.35, H. 7.41; N, 22.76.

23 EXAMPLE 88 7 g. of 7-[fi-hydroxyy-(N-benzoylpiperazino)-propyl]-theophylline was added to 70 ml. of conc.hydrochloric acid and heated to hydrolyse. 3.2 g. of 7-(8-hydroxy-y-piperazinopropyl)-theophylline thus obtained, 1.6 g. ofp-methoxybenzylchloride and 1.1 g. of triethylamine were added to 40 ml.of ethanol and treated in the same manner as in Example 73 to give 3.5g. of 7-[ S-hydroxy- 'y {N-(p-methoxybenzyl)-piperazino}propyl]-theophylline which wasrecrystallized from methanol. M.P. 151.5 152.5 C.

Elemental analysis-Cale. as C H N O (percent): C, 59.71; H, 6.83; N,18.99. Found (percent): C, 59.62; H, 6.81; N, 19.15.

EXAMPLE 89 5.6 g. of 7-[,B-hydroxy-y-(N-formylpiperazino)-propyl]-theophylline was added to 60 ml. of causticsoda solution and hydrolyzed. 3 g. of the crude 7-(B-hydroxy-'-piperazino-propyl)-theophylline thus obtained, 1.4 g. ofphenylethylchloride and 0.7 g. of anhydrous potassium carbonate wereadded to ml. of ethanol and treated in the same manner as in Example 74to give 3 g. of 7-[B-hydroxy-v-(Nphenylethylpiperazino)-propyl]-theophylline which was recrystallizedfrom ethanol. M.P. 1485-1495 C.

Elemental analysis.-Calc. as C H N O (percent): C, 61.95; H, 7.09; N,19.70. Found (percent): C, 61.81; H, 7.23; N, 19.65.

EXAMPLE 90 To 60 ml. ethanol was suspended 10 g. of 7-(ti-hydroxy- 'ypiperazino-propyl)-theophylline di-p-toluenesulfonate into which ammoniagas was introduced to allow conversion into free base and the resultingammonium sulfonate was filtered all. To the filtrate were added 1.6 g.of 2- vinylpyridine and 0.9 g. of glacial acetic acid and subjected toreflux under heating for 7 hours. After distillation of the solvent, theresidue was dissolved in chloroform and WflShtd with 10% caustic sodasolution and subsequently with water and dried. After removal ofchloroform by distillation, the residue was recrystallized from ethylacetate to give 5.1 g. of 7-[B-hydroxy-'y-{N(2-pyridylethyl)-piperazino}-propyl]-theophylline. M.P. 169.5-170.5 C.

Elemental analysis.Calc. as C21H29N703 (percent): Cale. C, 59.00; H,6.84; N, 22.93. Found (percent): C, 59.10;}1, 6.86; N, 22.92.

EXAMPLE 91 18 g. of ,6-hydroxy-' -ch1oropropyl-piperazine and 7.2 g. ofanhydrous potassium carbonate were added to 30 ml. of ethanol to react.32 g. of 7-[( 6hydroxy-'y-piperazino)-propyl]-theophylline thusobtained, 16 g. of pchlorobenzylchloride and 11 g. of triethylamine wereadded to ml. of ethanol and treated in the same manner as in Example 74to give 33 g. of 7-{fi-hydroxy- -{N -(p chlorobenzyl) piperazino}propyljl-theophylline which was recrystallized from ethanol. M.P. 149151C.

Elemental analysis-Cale. as C H N O (percent): C, 56.44; H, 6.09; N,18.80. Found (percent): C, 56.32; H. 6.2];N, 18.87.

EXAMPLE 92 10 g. of7-[fi-hydroxy-v-(N-formylpiperazino)-propyl]-theophyllir1e was added to100 ml. of conc. hydrochloric acid and heated to hydrolyse. 4.4 g. ofthe crude 7-(,8-hydroxy-v-piperazino-propyl)-theophylline thus obtained,2.2 g. of m-chlorobenzylchloride and 1 g. anhydrous potassium carbonatewere added to ml. of ethanol and treated in the same manner as inExample 74 to give 4.7 g. of 7-[fl-hydroxy-v-{N-(m-chlorobenzyl)-piperazino}-propyl]-theophylline which wasrecrystallized from ethanol. M.P. 160l60.5 C.

Elemental analysis.Calc. as C H ClN O (percent):

24 C, 56.44; H, 6.09; N, 18.80. Found (percent): C, 56.32; H, 6.16; N,18.93.

EXAMPLE 93 10.7 g. of 7-[fi-hydroxy-v-(N-ethoxycarbonylpiperizino)-propyl]-the0phylline was added to 150 ml. ofoonc. hydrochloric acid and heated to hydrolyse. S g. of 7-(fl hydroxy--piperazinopropyl]-theophy1line thus obtained, 3.9 g. ofa-chloromethylnaphthalene and 3.7 g. of anhydrous potassium carbonatewere added to 100 m]. of ethanol and treated in the same manner as inExample 74 to give 7.2 g. of crude 7-[l3-hydroxy- -{N-(a-naphthalenomethyl)-piperazino}-propyl]-theophy1line. The resultantproduct was then dissolved in ml. of absolute ethanol containing acalculated amount of hydrogen chloride and the precipitate thus formedwas filtered off to give 6 g. of 7 B-hydroxy-y-{N (wnaphthalenomethyl-piperazino}- propyll-theophylline dihydrochloride which whenrecrystallized from ethanol decomposes at 272-274 C.

Elemental analysis-Cale. as C H N O -2HCl (percent): C, 56.07; H, 6.02;N, 15.69. Found (percent): C, 55.81; H, 6.28; N, 15.34.

EXAMPLE 94 To 75 ml. of anhydrous ether were added 7.4 g. of 7-[43-hydroxy--y-{ N m-chlorobenzyl )-piperazino}-propyl] theophyllineobtained in Example 25 and 2.9 g. of benzoyl chloride and subjected toreflux for 10 hours under heating and stirring. After cooling, benzenewas distilled off and the residue was dissolved in chloroform, treatedwith 10% sodium carbonate solution, washed with water and dried. Afterdistilling 01f chloroform, the residue was recrystallized from methanolto give 9 g. of 7-[fl-benzoyloxy 'y {N-(m-chlorobenzy1)-piperazino}-propyl]-theophylline. M.P. 139.5 140 C.

Elemental analysir.-Calc. as C H CIN O, (percent): C, 61.03; H, 5.67; N,15.25. Found (percent): C, 60.77; H, 5.56; N, 14.97.

EXAMPLE 95 In 15 ml. of dried pyridine was dissolved 7 g. of 7-[13-hydroxy 'y {N -(p-methylbenzyl)-piperazino}-propyl]- theophyllineobtained in Example 26 and into the solution 3 g. of benzyl chloride wasdropped under ice cooling and stirring and subsequently heated at 50 C.for 4 hours. After cooling, the resulting precipitate was dissolved inchloroform, treated with 10% sodium carbonate solution, washed withwater and dried. After removal of the solvent by distillation, theresidue was recrystallized from methanol to give 7.6 g. of7-[B-benzoyloxy- -{N -(pmethylbenzyl) piperazino} propyl]-theophylline.M.P. 122-123 C.

Elemental analysis.Calc. as C H N 0 (percent): C, 65.64; H, 6.64; N,15.84. Found (percent): C, 65.46; H, 6.63; N, 15.63.

Example 96 To 75 ml. of anhydrous benzene were added 7.5 g. of 7- l,i-hydroxy-y-(N -benzyl-piperazino)-propyl] theophylline obtained inExample 23 and 3.1 g. of benzoylchloride and subjected to reflux for 6hours under heating and stirring. Benzene was then distilled off and theresidue was dissolved in chloroform, treated with 10% sodium carbonatesolution, washed with water and dried. After removal of chloroform bydistillation, the residue was recrystallized from methanol to give 6.5g. of 7-[fl-benzoyloxy-y-(N -benzyl-piperazino)-propyl]-theophylline.M.P. 149150.5 C.

Elemental analysis-Cale. as C H N O (percent): C, 65.10; H, 6.24; N,16.27. Found (percent): C, 64.99; H, 6.32; N, 16.21.

EXAMPLES 97 TO 108 The following products were obtained in the samemanner as in Example 96.

TABLE 4 Obtained b Example Number Product Theophylline derivatives (g.)Ex. N

97 7-{B benzoyloxy-'y-lN -(p-chlorobenzyl)- 7-[fl-hydroxy -[N 4-chlorobenzyl). 19

plperezmo l-propyH-theophylline. piperazlno l -propylY-theophylline(8.2).

98- 7-lB benz0 yl0xy--y-l N '(o-chl0robenzyl)- 7-lB-hydroxy- 4N(ochlorobenzyl)- 24 piperazinol-propyl]-theophylline.piperazlnol-propyll-theophylline 99 7-lB -benwyloxy--/-(N -phenyl-ethy1-7-(fi-hydr0Xyy-(N -phenyl ethyl piperazino) 20 plperazino)propyH-theophylline. propyll-thmphylline (8).

100- 7-m-benzoyloxy--r-lNdp-lsopropylbenzyh- 7-[fi-hydroxy-'1-(N-(p-lsopropylbenzyn- 22 piperazino l-propyH-theophylline. pipcrazino I-propyl]-theophylllne (7) 101 7-lfl-benzoyloxy-'y-(N -uchlorobenzyl-7-[fl-hydroxy-y-(N p-chlorobenzyl pipcrazino)- 80hydrazino)-propy1]-theophylline. propyl]-theophylllne (4.1.)

102 7-(fl-b nzeyloxy y-(N-IJ-1s0pr0pylbenzyl T-IB-hydroxy- -(N -piso myl benzyl 31 piperazlno)-propyll-theophylline. plperazino)-pr0pYl]-the0phy1line (2) 103 7-lfl-benzoyloxy-v-(N -o ehlorobenz l 7-[Bhydr0xy--r-(N -o-chlorobenzyl 2 plperazlno) -propyl]-theophylhne.piperezino) -propyll-theophylline [3) 1047-[fl-benzoyloxy-y-(N-p-methylbenzyl 7-[fl-hydroxyy-(N -p-methylbenzyl83 plperazlno)-propyl) the0phylllne. piperazino)-propyll-theophylline(5).

105- T-B-benzoylmy-q-(I U-beuul plperazinol- 7-[fl-hydmxyw-(N benzylplperazlno)- g4 propyll-theophylline. propyll-theophylline (3.7).

106 7-[B-henz0yloxy-1-(N phenyl ethyl 7-lfi-hydroxy-y-(N phenyl ethylpiperazino)- B9 piperezlno)propyll-theophylline. propylHheophylllne(1.5).

107 7-[B-benzoyloxy-y-(N -m-chlorobenzyl 7-lB-hydroxy-v-(N-m'chlorobenzyl 92 piperazlno)-propyl]-theophylline.piperezlno)-propyl]-theophylline (2).

108 7-[fi-benzoyloxy-v-(N -ethoxy carbonyl 7-lfl-hydroxy-v-(N -ethoxycarbonyl plperazin0)-pr0pyl]-theophyl1ine.piperazino)-pr0pyl]-theophyl11ne (5).

Properties of product Analysis, percent Benzoyl Calculated Found Examplechloride Solvent used Yield Number used (g.) (ml.) (g.) C H N C H N Ml.0.)

AS! CzaHarClNnO; 97- 3.1 Anhydro s 7-3 61-03 5-67 15.25 .18 5.63 15.25155-157 (methanol).

benzene (81) A8: CraHuClNiOt 98 5 Anhydrous 9.1 61-03 5-67 15.25 60.895.63 14.91 141-142 (methanol).

benzene (100) As: C29H5|N10l 99 3.3 Anhydrous 9-7 65-64 6. 46 55.37 6.47 15.16 1555-1565 (methanol).

benzene As: CsiHnNeOt 100, 2.5 Anhydrous 7 66-65 6.86 15.04 66.39 6.9314. 98 91-92 (methanol).

benzene (70) AS: CzgHnClNuOl 101 1-6 Anhydrous 3.6 61-03 5-67 15.2561.21 5.65 15.13 155-156 (methanol).

benzene (40) AS! CnHggNnOt 1[)2 2.1 Anhydrous 2.1 66.65 6. 86 15.0466.79 7.00 15.15 91-92 (methanol).

benzene (20) AS: ClflHllClNoOl 103 1 Anhydrous 2.8 61.03 5.67 15.2561.11 5.72 15.31 141-142 (methanol);

benzene (30) As: CznHuNuDq 104 1.6 Anhydrous 5-5 65.64 6.46 15.84 65.556.32 15.99 1495-1505 (methanol).

benzene (50) As: CnHnNnDi 105 1.6 Anhydrous 3-3 65-10 6.24 15.27 65.226. 38 16.15 149.5-1505 (methanol).

benzene (38) As: CfllI-HNO 106- 1.5 Anhydrous 1.5 65.64 6.46 15.84 65.786.50 15.71 1555-1565 (methanol).

benzene (20) AS: CagHuClNqOt 107 1.8 Anhydrous 1.3 61.03 5-67 15- 2561.21 5. 82 15.33 -140 (methanol).

benzene (20) AS! CuHmNoOg 108 2.2 Anhydrous 5.1 57.82 6.07 16.86 57.776.05 16. 92 176-177 (methanol).

benzene (50) EXAMPLE 109 and subjected to reflux under heating andstirring for 5 75 hours. After cooling, the reaction product wasfiltered and the mother liquor was concentrated under reduced pressure.The residue was recrystallized from ethyl acetate to give 1.8 g. of7-[fl-acetyloxy-y-(N -bcnzylpipcrazin0)- propyH-theophylline. M.P.l53-154 C.

Elemental analysis.Calc. as C H N O (percent): C, 60.78; H, 6.65; N,18.49. Found (percent): C, 61.13;

EXAMPLES l10l20 28 the acid-addition salts and quaternary ammonium saltsthereof, wherein R is selected from the group consisting of benzyl,methylbenzyl, isopropylbenzyl, chlorobenzyl and phenylethyl, and R isselected from the group con- 5 sisting of hydrogen, acetyl and benzyl.

2. The compound according to claim 1 which is: 7-[13- hydroxy 7 -.{N(o-chlorobenzyl)-pipcra.zino}-propyl] The following products wereobtained in the same way as described in Example 96. thcophylline.

TABLE 5 Example Obtained Number Product Theophylliuc derivatives (g.) byEx. No.

110 T-[d-acetyloxy-M N -(p-chlorobeuzyn- 7 [fl-hydroxy-'y-( N-(p-chlorobcnzyn- 19 piperazmo l -propyl] thcophy1line. pipcrazinol-propylI-theophyllinc (2) 111 T-[fl-acetyloxar-y-iN*(m-chlorobcnzy1]-7fl-hydroXy-7-N -(m-chlorobenzyl)- 31 plperaziuo propyl] thcophyllinc.piperazinmpropybtheophyllinc (10).

112 T-IB-acctyloxy-vl-N -(pdsopropyl benzyl)- 7-[;1hydroxy- -(N-(pisopropyl benzyD- 32 piperazino l -propyl]-theophylllne.piperazino1-pr0py1l-theophylline (10).

113 7-[,6-acetyloxy-'y-(N henyl ethyl 7-[Bhydr0xy-v-(N -pl1enyl ethyl 38plpemzino)-propyl -thephy1line. piperazlno)-propyl1the0phylliue (9).

114 l-lfi -acetyloxy-w-(N -p-chlorobenzyl 7-[8hydrox --r-(N-p'chlorobenzyl B0 piperazino)-propyl]-the0phy1line.piperazino)-propyl1-theophyllinc 115 I-[fi-ucetyloxy-ydN-is0pr0pylhcnzy1 T-{B-hydroxy-y4N -pdsoproplylbcnzyl 81p1pcrazino)-propyl -theophylliue. pl pcrazino) -pr0pyl]-the0 p ylline(2).

116 7-16-acetyloxy--y-(N -o-chlorobcnzyl T-[Bhydmxy-y-(N -o-chlorobenzyl82 piperazino-propyll-theophylline. pipcrazino-propyll-thcophylline (2).

117 T-LB-acctyloxy-y-(N -benzylp1pcrazino)- 7 {fi-hydroxy-r-(N -benzylpiperazino)- 84 propylj-theophylline. pmpyH-theophylllne (2).

118 T-[fi-acetyloxy-y-(N hanyl ethyl T-[H-h th-OXy- -(N pheuyI ethyl 89piperazlno)-propyl theophyllinc. p1pcrazino)-propyll-theophylline (1.5)

119 7-[fl-acety1oxy--y-lN -(m-chlorobenzyn- 7-lfl-hydroxy-v-lN(m-ch1or0benzyl)- 92 plperazino l -propyll-theophylline. pipcrazino}-propyl]-theophylline (2).

120 T-[B-acctyloxy-y-(N -ethoxy carbonyl- 7-[fl-hydr0xy-7-(N -cthoxycarbonyl- 50 piperazino)-propyl]-the0phylline.pipr'razluo)-propyl]-theophyllinc (5).

Properties 01 product Analysis, percent Anhydrous Acetic CalculatedFound Example sodium anhydrlde Yield Number acetate (g.) (ml.) (g.) C HN C H N Ml. 0.)

As C2lH2DClNuO 110 1 1. 8 56.50 5.98 17.19 56.29 5. 88 17.23 148449(ethyl acetate).

AS CzaHzoClNnOt 111 5 5D 10. 4 56.50 5.118 17.19 66. 42 6.21 17.30152-153 (ethyl acetate);

AS CMI MO 112 5 50 8.3 62.88 7.31 16. 92 62.71 7.25 17. 13 134435 (ethylacetate).

As CuHszNsOi 113 4. 6 7 61.51 6. 88 17.94 61.39 6.92 17. 78 133-134(ethyl acetate).

AS CzaHzqClNsOl 114 2. 5 26 4. 5 66. 56 5. 98 17. 19 56.31 6.01 17.14148.5-149 (ethyl acetate).

As CnHu uOA 115 1 1D 1. 7 62. S8 7. 31 16. 92 62. 81 7-11 16. 76 134-135(methanol).

AS CzaHzuClNeO; 116 l 10 1.5 56. 5.98 17 19 56. 62 5. 87 17.13 158-160(ethyl acetate).

AS CzsHmNoOd 117 l 10 1.5 60.78 6.65 18.49 60.66 6.61 18. 411 153-154(ethyl acetate).

As CzlHazNcol 11S 0.8 8 1.1 61. 51 6.88 17.94 61.23 6.75 17.84133.5134.5 (ethyl acetate).

As C2sH2iC NeQ4 116 1 1O 1. 5 56. 50 5. 9B l7. 19 66. 29 6. 03 17- 201525-15315 (ethyl acetate).

AS CrnHzgNeO; 120 2.5 25 5 52. 28 6.47 19. 26 52.20 6. 46 19. 23 128-129(ethyl acetate).

What is claimed is:

1. A compound selected from the group consisting of:

i \OR, L/

CHIC'HCHr-N :6. The compound according to claim 1 which is: 7-[8-hydroxy 'y-{N (p-isopropylbenzyl -piperazino} -propyl theophylline.

7. The compound according to claim 1 which is: 7-[3- hydroxy'y-{N*-(p-methoxybenzyl)-piperazino}-propyl]- theophylline.

8. The compound according to claim 1 which is: 7-[18- hydroxy 1 (Nphenylethylpiperazino)-propyl]-theophylline.

9. The compound according to claim 1 which is: 7-[3- bcnzoyloxy 1 (N-benzylpiperazino)-propyl]-theophylline.

10. The compound according to claim 1 which is: 7-[flbenzoyloxy 'y-{N(o-chlorobenzyl)-piperazino}-propyl]- thcophylline.

11. The compound according to claim 1 which is: 7-[B- benzoyloxy 7 {N(m-chlorobenzyl)-piperazino}-propyl -theophylline.

12. The compound according to claim 1 which is: 7-[flbenzoyloxy -{N(p-chlorobenzyl -piperazino}-prpyl theophylline.

13. The compound according to claim 1 which is: 7-[fibenzoyloxy 7 {N(p-methylbenzyl)-piperazino}-pro pyi] -iheophylline.

14. The compound according to claim 1 which is: 7-[13- benzoyloxy {N-(p-isopropylbenzyl)-piperazino}-propy1]-thcophylline.

15. The compound according to claim 1 which is: 7-[5- benzoyloxy (NphenyLeth I-pipcraZinO)-propyl]-theophyllinc.

16. The compound according to claim 1 which is: 7-[5- acetylozy 'y- N-bcnzylpiperazino -propyl]-theophy1line.

17. The compound according to claim 1 which is: 7-[flacetyloxy 7 {N-(o-chlorobeuzyl)-piperazino}-propyl]- theophylline.

18. The compound according to claim 1 which is: 7-[flacetyloxy-{N*-(m-chl0robenzyl)-piperazino}-propyl]- theophylline.

19. The compound according to claim 1 which is: 7-[fiacetyloxy y{N(p-chlorobenzyl)-piperazino}-propyl]- theophylline.

20. The compound according to claim 1 which is: 7-[flacetyloxy 'y {N(p-isopropylbenzyl)-piperazino}-propyl]-theophylline.

21. The compound according to claim 1 which is: 7-[flacetyloxy 7 (Nphenylethylpiperazino)-propyl]-theophylline.

References Cited UNITED STATES PATENTS 2,641,598 6/1953 Moussalli et al260-253 2,924,598 2/1960 Bestcan ct al 260-253 3,124,579 3/1964 Yoshidaet a]. 260256 NICHOLAS S. RIZZO, Primary Examiner A. M. TIGHE, AssistantExaminer

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF: